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Hypoxia-induced endothelial dysfunction in apolipoprotein E-deficient mice; effects of infliximab and l-glutathione

DOI: 10.1016/j.atherosclerosis.2014.08.021
  • Hypoxia
  • Free Radicals
  • Endothelium
  • Atherosclerosis
  • Progenitor Cells
  • Biology


Abstract Objective Obstructive sleep apnoea (OSA) has been implicated as a risk factor for atherosclerosis. The aim of our study was to examine the effects of chronic intermittent hypoxia in apoE−/− mice serving as model of OSA on endothelial dysfunction and oxidative stress and to evaluate the reversibility of hypoxia-induced changes under anti-inflammatory infliximab and anti-oxidative l-glutathione. Methods ApoE−/− mice were divided into 4 groups (n = 9 each): 1. intermittent hypoxia 8 h/day for 6 weeks, 2. intermittent hypoxia + injections of infliximab, 3. intermittent hypoxia + injections of l-glutathione, 4. normoxia = control. Results Endothelial function was impaired under hypoxia compared to control. Application of infliximab and l-glutathione improved it to a level of control. The percentage of endothelial microparticles increased under hypoxia compared to other groups. Levels of NADPH oxidase 2-derived reactive oxygen species were approximately 9 times higher in the hypoxia group. The number of sca-1/flk-1+ endothelial progenitor cells was higher in bone marrow and lower in blood under hypoxia vs. other groups. Stromal cell derived factor-1alpha- and matrix metalloproteinase-9-dependent release of these cells from bone marrow was attenuated under hypoxia. The number of DilacLDL+/lectin + early outgrowth progenitor cells and that of colony forming units from these cells were higher under hypoxia. Atherosclerotic plaques in the aorta were more frequent under hypoxia and control in comparison with both drug groups. Conclusion Intermittent hypoxia contributes to endothelial dysfunction by the local increase in reactive oxygen species and reduction of the peripheral repair capacity. Infliximab and l-glutathione prevent hypoxia-induced vascular and extravascular changes.

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